scholarly journals The Murine Natural Cytotoxic Receptor NKp46/NCR1 Controls TRAIL Protein Expression in NK Cells and ILC1s

Cell Reports ◽  
2018 ◽  
Vol 22 (13) ◽  
pp. 3385-3392 ◽  
Author(s):  
Sam Sheppard ◽  
Iona S. Schuster ◽  
Christopher E. Andoniou ◽  
Clement Cocita ◽  
Thomas Adejumo ◽  
...  
Keyword(s):  
Protein Expression ◽  
Nk Cells ◽  
Trail Protein ◽  
Natural Cytotoxic

scholarly journals PD-1 in human NK cells: evidence of cytoplasmic mRNA and protein expression

2018 ◽  
Vol 8 (3) ◽  
pp. 1557030 ◽  
Author(s):  
Francesca R. Mariotti ◽  
Stefania Petrini ◽  
Tiziano Ingegnere ◽  
Nicola Tumino ◽  
Francesca Besi ◽  
...  
Keyword(s):  
Protein Expression ◽  
Nk Cells ◽  
Mrna And Protein Expression

scholarly journals MicroRNA regulation of STAT4 protein expression: rapid and sensitive modulation of IL-12 signaling in human natural killer cells

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6793-6802 ◽  
Author(s):  
Yong Huang ◽  
YingFeng Lei ◽  
Hai Zhang ◽  
LiChao Hou ◽  
Mingjie Zhang ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Protein Expression ◽  
Nk Cells ◽  
Natural Killer ◽  
Signaling Pathway ◽  
Initial Increase ◽  
Microrna Regulation ◽  
Human Natural Killer Cells ◽  
Ifn Γ ◽  
Regulatory Effects

Abstract IL-12 exerts several regulatory effects on natural killer (NK) cells by activating IL-12 signaling. IL-12 signaling is tightly auto-regulated to control its onset and termination, with prolonged IL-12 treatment resulting in IL-12 hyporesponsiveness. However, the mechanisms underlying IL-12 auto-regulation are still unclear. In this study we report that prolonged IL-12 treatment significantly up-regulates microRNAs (miRNAs), including miR-132, -212, and -200a in primary human NK cells. This up-regulation correlates temporally with gradually decreasing STAT4 levels and decreasing IFN-γ expression, after an initial increase within the first 16 hours of IL-12 treatment. The IL-12 hyporesponsiveness is dependent on IL-12 concentration, and associated up-regulation of miR-132, -212, and -200a. Furthermore, IL-12–hyporesponsive cells regain responsiveness of IFN-γ production 24 hours after IL-12 removal, which correlates with decreases in miR-132, -212, and -200a levels. Overexpression of miR-132, -212, and -200a by transfection into NK cells mimics IL-12 priming, inducing IL-12 hyporesponsiveness, whereas transfection of miR-132, -212, and -200a inhibitors largely abolishes IL-12 induction of IL-12 hyporesponsiveness. These data suggest that miR-132, -212, and -200a up-regulation during prolonged IL-12 treatment, negatively regulates the IL-12 signaling pathway by reducing STAT4 expression in primary human NK cells.

scholarly journals METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Song ◽  
Jiaxi Song ◽  
Ming Cheng ◽  
Meijuan Zheng ◽  
Tian Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Tumor Development ◽  
Mapk Signaling ◽  
Gene Encoding ◽  
Tumour Immunity ◽  
M6a Rna Methylation ◽  
And Function

AbstractNatural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N6-methyladenosine (m6A) methylation) is unclear. Here we report decreased expression of the m6A “writer” METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m6A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m6A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.

A Novel CD94+ Immature NK Cell Population Based on NKp80 Expression with ILC3-like Features in Human Secondary Lymphoid Tissue

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 751-751
Author(s):  
Steven D Scoville ◽  
Karen Keller ◽  
Bethany Mundy-Bosse ◽  
Michael A. Caligiuri ◽  
Aharon G. Freud
Keyword(s):  
Protein Expression ◽  
Nk Cells ◽  
Cell Population ◽  
Lymphoid Tissue ◽  
Nk Cell ◽  
Ex Vivo ◽  
Differentiation Potential ◽  
Secondary Lymphoid Tissue ◽  
Stage 4 ◽  
Mrna And Protein Expression

Abstract Natural killer (NK) cells are important for their innate ability to identify and kill cancer cells without previous stimulation. However, many of the mechanisms concerning their differentiation from immature precursor cells are still unknown. Elucidation of these pathways are critical to improving targeted therapies that can both activate as well as overcome inhibitory pathways that prevent an effective response. NK cells are thought to develop in secondary lymphoid tissue (SLT) through five stages distinguished by the expression of CD34, CD117, CD94, and CD16. While virtually all NK cells in blood express the pan-NK cell activating receptor, NKp80, we have discovered a distinct Lin CD94+NKp80-CD16- population that is selectively enriched in SLT. The NKp80- population appears to comprise those cells “in transit” between stage 3 (CD117+CD94-) and stage 4 (CD117loCD94+) when evaluating CD94 and CD117 expression among Lin-CD34- cells by flow cytometry. These ex vivo data suggest that this NKp80- population may represent a novel NK cell developmental intermediate (NKDI). SLT-derived NKp80- cells lack cytolytic granules, show minimal cytotoxicity, and produce negligible amounts of interferon-gamma when compared to NKp80+ NK cells in SLT and blood. In addition, NKp80- cells have lower mRNA and protein expression of TBET and EOMES compared to NKp80+ NK, while expressing these factors at higher levels compared to stage 3 cells. Unexpectedly, the NKp80- population also demonstrates Group 3 innate lymphoid cell (ILC3)-like features ex vivo with expression of surface interleukin-1 (IL-1) receptor 1 and CD127 and mRNA and protein expression of the ILC3-associated transcription factors, AHR and RORC. Moreover, following overnight stimulation with IL-1-beta and IL-23, NKp80- cells produce IL-22, albeit at lower concentrations compared to stage 3 cells. Collectively, these data identify NKp80 as a surrogate marker of functional competence during in vivo human NK cell development and provide evidence for the existence of at least two distinct maturation steps within the previously described stage 4 NK cell population in SLT. Since CD94 expression is currently considered to be NK-restricted, these findings raise new questions regarding the developmental relationship between NK cells and ILC3 in humans. In addition, as ILC3s are primarily used to stimulate an anti-microbial defense while NK cells are functional anti-cancer effector cells, defining the differentiation patterns of these cells can have impacts in both of these areas of research. Studies are ongoing to investigate the in vitro differentiation potential(s) of this novel SLT-derived Lin-CD94+NKp80-CD16- population. Disclosures No relevant conflicts of interest to declare.

Su.32. Expression of Natural Cytotoxic Receptors by NK Cells from HCV-infected Patients

2008 ◽  
Vol 127 ◽  
pp. S134-S135
Author(s):  
Angela Conesa ◽  
Carmen Millet ◽  
Isaac Blanca ◽  
Irma Machado ◽  
Roberto León ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Cytotoxic

CS1 Is Expressed on Myeloma Cells from Early Stage, Late Stage, and Drug-Treated Multiple Myeloma Patients, and Is Selectively Targeted by the HuLuc63 Antibody.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 660-660 ◽  
Author(s):  
Susann Szmania ◽  
Balaji Balasa ◽  
Priyangi Malaviarachchi ◽  
Fenguhuang Zhan ◽  
Yongsheng Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Protein Expression ◽  
Nk Cells ◽  
Late Stage ◽  
Plasma Cells ◽  
Nk Cell ◽  
Early Stage ◽  
High Dose ◽  
Myeloma Cells

Abstract Introduction: One-third of multiple myeloma (MM) patients exhibit high-risk features such as abnormal cytogenetics, high LDH, amplification of CKS1-B or spiked expression of MAF, MAF-B or FGFR3. While not affecting complete response rates, median durations of event-free and overall survival, even with high-dose melphalan-based tandem autotransplants of such patients, do not exceed 24 mo and 36 mo, compared to 60 mo and ≥ 90 mo for the remainder. Monoclonal antibody (mAb)-mediated therapy may target a chemotherapy-resistant myeloma cell pool. CS1 (CD2 subset 1, CRACC, SLAMF7), a member of the CD2 family of cell surface glycoproteins, exhibits high-level expression on primary myeloma cells, indicating that CS1 is a potential target for treatment in MM. Methods: Gene expression was assessed using an Affymetrix GeneChip array. Protein expression was measured by flow cytometry, and immunohistochemistry (IHC), using HuLuc63, a novel humanized anti-CS1 mAb. HuLuc63-mediated lysis of myeloma cells via antibody dependent cellular cytotoxicity (ADCC) was measured by 51Cr-release. Results: CS1 mRNA was detected in >95% of CD138+ purified plasma cells from >95% of healthy donors, newly diagnosed myeloma patients, and those with relapsed myeloma (Fig. 1a). CS1 remained highly expressed in patients following VDTPACE treatment, albeit at a reduced level. CS1 expression was also high following bortezomib (Velcade®) treatment, with a subset of patients showing increased expression post-treatment. CS1 protein expression on primary myeloma cells was confirmed by flow cytometry, while IHC analysis of normal tissues revealed anti-CS1 staining primarily on CD138+ tissue plasma cells. Finally, we determined that HuLuc63 could induce killing of myeloma cells using purified allogeneic NK cells (Fig. 1b). Blocking the Fc receptor greatly reduced this activity indicating an ADCC mechanism. Killing of myeloma targets was also observed in autologous systems suggesting that HuLuc63 can overcome KIR-mediated NK cell inhibition of autologous NK cells. In summary, we observed high mRNA and protein expression of CS1 in myeloma from early stage, late stage, and treated patients, and showed enhanced lysis of myeloma cells in vitro with HuLuc63. Our data support the potential clinical utility of CS1-targeted therapy. HuLuc63 will be entering a phase I clinical trial for advanced myeloma patients. Figure 1a. CS1 mRNA is highly expressed in CD138+ purified plasa cells. Figure 1a. CS1 mRNA is highly expressed in CD138+ purified plasa cells. Figure 1b. CS1 antibody enhances killing of myeloma cells by allo - NK cells. Figure 1b. CS1 antibody enhances killing of myeloma cells by allo - NK cells.

Systemic Delivery of Nanoliposomal Ceramide Displays Anti-Leukemic Activity in a Rat Model of Large Granular Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3999-3999
Author(s):  
Xin Liu ◽  
Lindsay Ryland ◽  
Jun Yang ◽  
Cesar Aliaga ◽  
James Kaiser ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Expression ◽  
Nk Cells ◽  
Cell Line ◽  
Rat Model ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Splenic Cells ◽  
Bone Marrow Blood ◽  
Lgl Leukemia

Abstract We have previously demonstrated that enhanced survival rather than increased proliferation accounts for the accumulation of natural killer (NK) cells in large granular lymphocyte (LGL) leukemia patients. To further elucidate the mechanism by which NK survival is enhanced, we analyzed leukemic NK cells isolated either from patient peripheral blood or rat splenic cells for altered expression of members of the inhibitor of apoptosis protein (IAP) family, which act as suppressors of apoptosis in a variety of human solid tumors and hematological malignancies. We now report that the IAP, survivin, was highly expressed in NK cells. In contrast, survivin was barely detectable in NK cells from the blood of normal human donors or the splenic cells from normal rats. We next asked if the lipid-derived second messenger, ceramide, which selectively induces apoptosis in cancer cells would diminish survivin protein expression. Treatment of NKL, a human NK-LGL leukemia cell line, or RNK-16, a rat NK-LGL leukemia cell line, with the cell-permeable, short-chain C6-ceramide (C6) in a pegylated liposomal formulation, led to cell apoptosis and diminished survivin protein expression, in a time and dose dependent manner. We next extended these in vitro studies to an in vivo rat model of NK-LGL leukemia. Systemic i.v. delivery of liposomal ceramide displayed significant anti-leukemia activity in a syngeneic Fischer F344 rat NK-LGL leukemia model that exhibits clonal expansion of CD3-CD8a+ lymphocytes. Over a 6-week treatment period, a well-tolerated dose of 40 mg/kg liposomal-C6, three times a week, elicited a 3 to 10- fold reduction in the weight of various lymphoid and non-lymphoid organs, compared with liposomal formulations that did not contain ceramide (ghost). Untreated or ghost-treated leukemic rats presented with lymphocytosis (LGL counts between 2 × 1011 and 3.5 × 1011/L), anemia and thrombocytopenia. Furthermore, the percentage of NK LGL cells, defined as CD3-CD8a+ by flow cytometry, was drastically elevated in the spleen, lymph node, thymus, bone marrow, blood, liver and lung in these leukemic rats, compared with their normal counterparts. In contrast, leukemic rats treated with liposomal ceramide had undetectable LGL cells in the blood and normal counts of red blood cells and platelets. Additionally, the CD3-CD8a+ NK cells in spleen, thymus and liver were found to be remarkably decreased, whereas the NK cells in bone marrow, blood and lung were within normal range. Collectively, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for anti-leukemic efficacy in a rat model of NK LGL leukemia, possibly via decreased survivin expression or signaling.

scholarly journals Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nicole Marquardt ◽  
Eliisa Kekäläinen ◽  
Puran Chen ◽  
Magda Lourda ◽  
Jennifer N. Wilson ◽  
...  
Keyword(s):  
Protein Expression ◽  
Nk Cells ◽  
Lung Tissue ◽  
Human Lung ◽  
Human Lung Tissue ◽  
Expression Signature
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